Studies on patient isolates of HIV-1 have correlated different patterns of cytotropism and virulence with the sero-positive pre-AIDS and AIDS phases of disease. Here we propose to study the evolution of HIV-1 envelope glycoproteins with respect to antibody responses. Two approaches will be used. (i) Viruses representing different phases of infection will be tested for relative susceptibility to neutralization by a panel of antibodies. (ii) Env-encoding sequences from the same viruses will be evaluated for their ability to raise neutralizing antibody. Envs to be studied will include Envs with different V3 loops or growth characteristics, serial Envs representing the progression from the healthy sero-positive to the AIDS phase of infection, and serial Envs from patients with long term non-progressive disease. Antibodies will be raised using a novel method of immunization that we have helped pioneer - gene gun delivery of Env-encoding plasmid DNA to the epidermis. These studies should contribute to the development of vaccines that control viruses representing different phases of infection. They should also resolve the extent to which neutralizing antibody plays a role in the selection of envelope phenotypes.